miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts.
5400 - 5412
Nucleic Acids Res
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Uncontrolled cell proliferation and cytoskeletal remodeling are responsible for tumor development and ultimately metastasis. A number of studies have implicated microRNAs in the regulation of cancer cell invasion and migration. Here, we show that miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer (BC), implicating a central role for it in cytoskeletal dynamics. Inhibition of miR-23b, using a specific sponge construct, leads to an increase of cell migration and metastatic spread in vivo, indicating it as a metastatic suppressor microRNA. Clinically, low miR-23b expression correlates with the development of metastases in BC patients. Mechanistically, miR-23b is able to directly inhibit a number of genes implicated in cytoskeletal remodeling in BC cells. Through intracellular signal transduction, growth factors activate the transcription factor AP-1, and we show that this in turn reduces miR-23b levels by direct binding to its promoter, releasing the pro-invasive genes from translational inhibition. In aggregate, miR-23b expression invokes a sophisticated interaction network that co-ordinates a wide range of cellular responses required to alter the cytoskeleton during cancer cell motility.
AuthorsPellegrino, L; Stebbing, J; Braga, VM; Frampton, AE; Jacob, J; Buluwela, L; Jiao, LR; Periyasamy, M; Madsen, CD; Caley, MP; Ottaviani, S; Roca-Alonso, L; El-Bahrawy, M; Coombes, RC; Krell, J; Castellano, L
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